Abstract

Rheumatology patients frequently note the occurrence of stressful or traumatic life
events prior to the onset of their illness and/or a relationship between stress and
disease flares. For our patients, identifying causal events could represent an effort
to give meaning to a chronic and often disabling disease, while noting a link between
stress and flares may proffer a sense of control. Whatever purpose the report of stress
as an etiological or maintaining factor may serve, the science exploring a causal
relationship between stress and autoimmune disease onset and course is expanding.
Moreover, stress can also induce symptoms such as pain via nonimmunological mechanisms.

Editorial

In the present issue of Arthritis Research & Therapy, de Brouwer and colleagues review the literature pertaining to experimental studies
targeting acute-phase reactivity in the stress-response systems of patients with rheumatoid
arthritis (RA) and systemic lupus erythematosus (SLE) [1]. The authors included only studies employing experimental stressors (psychosocial,
cognitive, exercise, and sensory/pain induction) to evaluate physiological responses
at three levels - the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal
(HPA) axis, and the immune system - in patients with RA and SLE.

Sixteen studies were identified [1]. The authors found inconsistent results regarding experimentally induced stress and
the ANS and HPA axis baseline levels and reactivity, but found some evidence for alterations
in immune functioning in patients compared with controls. They noted that the most
consistent finding in response to experimentally induced stress was an increase in
the number of natural killer cells, but this may not be surprising because natural
killer cell trafficking is very sensitive to stress hormones such as catecholamines.
The authors note, however, that many of the studies possessed methodological problems
of their own. Most studies were underpowered (that is, small sample sizes) and some
failed to control for potential confounders such as medication use, age, sex, psychiatric
comorbidity, stress coping/appraisal and abuse history. In patients with rheumatologic
illness, the presence of depression and a history of abuse are relatively common and
have been associated with alterations in the stress-response and immune systems [2,3].

The results from the present review of the effects of stress in RA and SLE suggest
that the findings in these disorders are congruent with a broader literature including
both animal models and clinical studies of other rheumatic disorders. A number of
different types of stress have been shown to induce arthritis in animal models [4]; however, such a relationship in humans is more tenuous.

Most studies are limited by the use of cross-sectional designs and the pitfalls associated
with self-report retrospective data, but their findings are still of interest. For
example, a study of Vietnam combat veterans with current post-traumatic stress disorder
(n = 2,490) found that they were at increased risk for autoimmune diseases (16.7%,
95% confidence interval = 7.9 to 29.3%) compared with those without post-traumatic
stress disorder (6.1%, P < 0.05) [5]. In that study, the combination of several stress-related conditions seemed to further
increase this risk, with 8.1% of these male veterans with both posttraumatic stress
disorder and comorbid depression, anxiety or other significant psychopathology reporting
a diagnosis of RA [5].

Other studies have contemplated a role for early life stressors in increasing vulnerability
to autoimmune disease. One recent study found that individuals reporting two or more
traumatic childhood events were at a 100% increased risk for rheumatic diseases compared
with those reporting no childhood trauma [6]. Further, a multitude of studies have described relationships between psychological
stress and poor outcomes in both RA and SLE including disease flares. The mechanisms
presumed to underlie these associations include stress-related changes in functioning
of the autonomic, neuroendocrine and/or immune systems.

Work performed to examine how stress modulates symptoms, especially pain, in other
nonautoimmune rheumatic conditions such as fibromyalgia might also be instructive
in elucidating the role of stress in symptom expression. From a vast array of experimental
studies it is reasonable to conclude that a variety of stressors may cause pain, that
pain may cause stress, and, more importantly, that a simple unidirectional relationship
between changes in stress-response function and pain and other symptoms probably does
not exist. Imaging studies of pain processing in fibromyalgia indicate that psychological
stress (that is, depression, anxiety) and pain are processed somewhat independently
in the central nervous system [7]. Supporting this conclusion are the clinical data indicating that drugs acting as
both antidepressants and analgesics (for example, tricyclics or serotonin-norepinephrine
reuptake inhibitors) are equally effective analgesics in chronic pain conditions in
patients with and without depression [8]. The lack of direct overlap in the central processing of stress and pain suggests
that the degree to which stress influences pain, and vice versa, may be moderated by individual factors such as cognitions, coping/appraisal and
social support [9,10].

In fibromyalgia, as well as in autoimmune disorders, symptom expression is likely
determined to a similar extent by genetic and environmental factors. Although there
have been efforts to link pain and subtle abnormalities in ANS and HPA system functioning
seen in individuals with fibromyalgia and other chronic pain syndromes, newer data
suggest much more complex interrelationships between these systems. Observable changes
in the ANS or HPA axis tone in some individuals may represent a baseline diathesis
or risk factor for the subsequent development of chronic pain, or the changes may
be due to pain itself or to the indirect effects of pain such as deconditioning secondary
to decreased exercise.

In summary, when our patients say that stress worsens their disease, they may be correct.
Although the study of stress is fraught with problems, there are clearly both immune
mechanisms (that is, psychoneuroimmunology) and nonimmune mechanisms (for example,
mechanisms operative in conditions such as fibromyalgia, either alone or comorbid
with autoimmune disorders) that may be responsible for increased disease activity
and/or symptom expression during periods of stress.